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Tetrahedron 64 (2008) 3372e3380 www.elsevier.com/locate/tet

Cyanamide: a convenient building block to synthesize 4-aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine systems via a multicomponent reaction
n a, R. Contreras-Rojas a, R. Miranda a, R. Hulme a,b,*, O.D.P. Zamora a, E.J. Mota a, M.A. Paste ndez b, J. Correa-Basurto b, J. Trujillo-Ferrara b, F. Delgado c,* I. Valencia-Herna
a

Departamento de Ciencias Quimicas, Facultad de Estudios Superiores Cuautitla n, Universidad Nacional Auto noma de Me xico, n Izcalli, Estado de Me xico, CP 54740, Mexico Avenida 1ro de Mayo s/n, Cuautitla b Escuela Superior de Medicina-IPN, Plan de San Luis y D az Miro n, Col. Santo Toma s, Me xico, D.F., CP 11340, Mexico c Departamento de Qu mica Orga nica, Escuela Nacional de Ciencias Biolo gicas, Instituto Polite cnico Nacional, Prolongacio n Carpio y Plan de Ayala, Casco de Santo Toma s, Me xico, D.F., CP 11340, Mexico Received 19 December 2007; received in revised form 21 January 2008; accepted 24 January 2008 Available online 31 January 2008

Abstract 4-Aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine derivatives were prepared using a multicomponent reaction by reacting a mixture of arene or heteroarenecarbaldehyde, 1,3-dicarbonyl compounds, and cyanamide under acidic conditions. The novelty of this approach derives from its use of cyanamide as a building block in a four-component Biginelli-type reaction. Varying the reaction conditions led to the formation of either N-(2-imino-6-phenyl-1,3,5-oxadiazinan-4-ylidene) cyanamide or 3,4-dihydropyrimidin-2(1H)-one. The type of heterocycle skeleton synthesized depends on the nature of the acid catalyst as well as the reaction conditions employed. 2008 Elsevier Ltd. All rights reserved.
Keywords: Cyanamide; Building block; Multicomponent reaction; 4-Aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine

1. Introduction In recent years, multicomponent reactions (MCRs) have emerged as a powerful strategy to construct structurally complex molecules from simple starting materials.1 Molecules synthesized by this method continue attracting the attention of medicinal and synthetic chemists.2 One of the most cited MCRs is the Biginelli reaction, which leads to the formation of 3,4-dihydropyrimidin-2(1H)-one (DHPM) derivatives using benzaldehyde, ethyl acetoacetate, and urea as starting materials.3 This reaction has been widely extended to include variations in all of its components,4 allowing access to a large number of multifunctionalized DHPM derivatives. For example,
* Corresponding authors. E-mail addresses: hulmerg@yahoo.com woodward.encb.ipn.mx (F. Delgado).

(R.

Hulme),

fdelgado@

an interesting reaction is the four-component approach, recently reported by Orru and et al., to synthesize DHPMs that are properly functionalized at the N-3 position, providing a pool of structurally diverse compounds of biological interest.5 Many of these derivative compounds have emerged as a class of therapeutic drugs with important pharmacological roles in medicinal chemistry, such as hexahydrotriazaacenaphthalenes (1),6 SQ 32926 (2),7 and HAP-1 (3).8 Although this reaction has been intensely explored, the construction of 4-aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine (aryl-CIDHPM) compounds (4) that are chemically analogous to the Biginelli compounds has not yet been reported. Interestingly, the above molecules possess the N-cyanoguanidinyl moiety in their structure, which is found in other biologically active molecules such as the potentially antimycotic agent N-cyanoiminopyrimidine (5),9 pinacidil (6), a KATP channel activator10 (Fig. 1), and other compounds containing the cyanoimino

0040-4020/$ - see front matter 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.01.087

R. Hulme et al. / Tetrahedron 64 (2008) 3372e3380

F O2N O R3O2C R2 N H 1 O R2 R3 N H 4 Aryl N H N CN N 5 N N N H CO2R R1 i-PrO N H 2 N O O NH2 EtO N H 3 O N N H N Cl

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building blocks.13 Therefore, the application of this approach to prepare aryl-CIDHPMs, its scope and limitations via systematic variation of arene or heteroarenecarbaldehyde and 1,3-diketone components, and the inuence of catalyst nature in the absence or presence of solvents are reported. 2. Results and discussion The initial efforts to synthesize aryl-CIDHPMs were based on the preparation of N-arylidenecyanoguanidine, a Michael acceptor that was chemically convenient to replace a-tosylsubstituted N-cyanoguanidines, the key intermediate in the synthesis of alkyl-CIDHPMs. In agreement with the accepted Biginelli mechanism,14 this species may form in situ under the Biginelli three-component reaction (B-3CR) conditions through the initial reaction of a mixture of arenecarbaldehyde and cyanoguanidine. The subsequent formation of the arylCIDHPMs theoretically could have been achieved by reacting the N-arylidenecyanoguanidine with an appropriate 1,3-dicarbonylic compound. Unfortunately, we were unable to prepare this compound using this method. However, recently Fischer et al. reported the synthesis of 2-arylaminopyrimidine derivatives through N-arylguanidine. This intermediate was appropriately synthesized from a mixture of cyanamide and aryl amines under strongly acidic conditions.15 The chemical explanation behind this process led us to attempt to form N-arylidenecyanoguanidine under similar conditions by replacing cyanoguanidine with 2 equiv of cyanamide in the presence of 1 equiv of arenecarbaldehyde, yielding the title compound after a subsequent reaction with a 1,3-dicarbonyl compound. The result was the development of a novel one-pot multicomponent reaction via a four-component approach to prepare aryl-CIDHPMs. In this multicomponent approach, an exploratory reaction composed of benzaldehyde 7a, ethyl acetoacetate 8a, and cyanamide 9 (50% in water) were reacted in a 1:1:2 molar ratio, respectively, in the presence of concd hydrochloric acid (pH w2) at reux conditions (EtOH, 4 h). The desired 2-cyanoimino-5ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydro-1H-pyrimidine 10a was obtained, although in very low yields (5%, Scheme 2, method a). The result may be rationalized by considering the substantial formation of cyanamidium cations and its corresponding hydrolysis to urea, according to the following equation:16
H 9 H3N N H2O O H2N NH2 CO2 + 2NH2

CN NH

N N H

CN N H

Figure 1. Biginelli-type and cyanoguanidine compounds with pharmacological activity.

functional group that have been found in pharmacologically active products.11 The most promising method to construct aryl-CIDHPMs is through the synthesis reported by Shutalev et al. for the obtention of 4-alkyl-2-cyanoimino-3,4-dihydro-1H-pyrimidines (alkyl-CIDHPMs).12 This approach implies the preparation of a-tosyl-substituted N-cyanoguanidines i. A subsequent reaction with potassium enolates of ethyl acetoacetate results in 5-ethoxycarbonyl-2-cyanimino-4-hydroxyhexahydropyrimidines ii, which yield the alkyl-CIDHPMs iii after dehydration under acidic conditions (Scheme 1). However, some of the drawbacks of this approach involve a relatively long synthetic pathway, lengthy reaction times, and purication steps that considerably reduce the efciency of the reaction and overall yields of these compounds.
R H O S OH + H2N O H2N N R CN 2-4 day water, rt Ts H2N i O N H CN TsOH/EtOH 1-2 h, reflux EtO N H 46-73% iii R N H N CN R= Me, Et, Pr NH N CN O O OEt / KOH 6-7 h, rt

63-94%

O EtO HO

N N H 51-80% ii

Scheme 1. Shutalev synthesis of alkyl-CIDHPMs.

More relevant to the present work is the novel methodology employed to synthesize aryl-CIDHPMs by a four-component Biginelli-type reaction based on replacing the cyanoguanidine with 2 equiv of cyanamide. It is worth mentioning that this protocol explored the use of cyanamide as a precursor of new ureatype building blocks to obtain structurally diverse Biginelli compounds, whereas most of the previously reported Biginelli reactions involve urea, thiourea, isourea, or guanidine as

This reaction is known to occur at pH <8.17 Therefore, weak acidic conditions that shift the equilibrium toward the cyanamide would inhibit ureide formation and probably improve the yield. Thus, the next catalytic system explored was a mixture of AcONa (1 equiv) and concd hydrochloric acid (in catalytic amount) at pH w5, which substantially improved the overall yield (40%, Scheme 2, method b). Since this process implies the in situ formation of AcOH, the possibility of better yields

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R. Hulme et al. / Tetrahedron 64 (2008) 3372e3380

O HN N H 11

H N CN

i= 50%

Method i

O EtO N H 12 g= 59%, h= 61% N H O Methods g, h EtO

7a O O + O 8a

H N 2 NH2 9 Methods a, b, c d, e, f EtO

O N N H 10a a= 5%, b= 40 %, c= 34 % d= 0%, e= 11 %, f= 15% H N CN

Scheme 2. Synthesis of compounds 10a, 11, and 12 through the 4-CR protocol using diverse reaction conditions. Reagents and conditions: method a: HCl/EtOH, method b: HCl/AcONa/EtOH, method c: AcOH/EtOH, method d: AcONa/EtOH, method e: acetate buffer (AcOH/AcONa/HCl, pH 5), method f: HCl/AcONa/ H2O, method g: TsOH/NH4Cl/EtOH, method h: AlCl3/EtOH, and method i: HCl/AcONa.

using AcOH alone was considered. However, the yield with AcOH was lower (34%, Scheme 2, method c) than that with method b, whereas no product was formed when the reaction was carried out in the absence of either AcOH or concd hydrochloric acid (0%, Scheme 2, method d). Since these experimental results show that the reaction is pH dependent, an acetate buffer was considered to be more appropriate. However, the yield of 10a did not improve (11%, Scheme 2, Method e), and unwanted by-products were observed, perhaps due to a competing acid-catalyzed hydrolysis of cyanamide to urea, known to happen under acetate buffer conditions.18 On the other hand, when the reaction was promoted with pure cyanamide using the conditions of method b, the overall yield was not improved (30%) and the corresponding product was not observed as a precipitate at the end of the reaction (similar to the results from method b). To obtain the desired compound, it was necessary to concentrate and cool the mixture for 24 h at 0  C. To further improve the yield, other solvents, such as water and methyl sulfoxide, were used without obtaining better results. When EtOH was substituted with water, the yields were substantially lower (15%, Scheme 2, method f), which was probably a consequence of a lack of reagent solubility and the hydrolysis of cyanamide to urea, known to be more effective in hydrochloric acid aqueous solution,18 while the reaction with methyl sulfoxide led to no detectable production of 10a. In an attempt to gain more complete understanding on the behavior of this reaction, we employed modied conditions, such as the use of TsOH/NH4Cl or AlCl3 as catalytic agent, as well as solventless conditions in the presence of concd hydrochloric acid and AcONa. In the former case, the Biginelli product, 5-ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one 12, was obtained at 59% with TsOH and

61% with AlCl3 (Scheme 2, methods g and h). This compound was spectroscopically identical to a sample prepared through the typical B-3CR protocol.3c When concd hydrochloric acid/AcONa and solventless conditions were used, the isolated product was N-(2-imino-6-phenyl-1,3,5-oxadiazinan-4ylidene) cyanamide 11 (50%, Scheme 2, method i). The proposed structure was consistent with the spectroscopic data obtained on the basis of NMR and MS experiments. The 1H NMR spectrum showed the presence of four magnetically different protons that appear as two singlet signals at 10.47 and 9.68 ppm and two doublet signals at 8.63 (3J6,52.4 Hz) and 5.63 (3J5,62.4 Hz) ppm. These signals were appropriately assigned to the NH groups bonded to C-2, NH-3, NH-5, and H-6, respectively. The multiple signals observed between 7.45 and 7.34 ppm were attributed to the ve protons of the phenyl moiety on C-6. The 13C NMR spectrum showed signals assigned to two nonequivalent C]N groups at 156.6 (C-4) and 150.6 (C2) ppm; carbons observed at 140.4 (C-10 ), 128.9 (C-40 ), 128.8 (C-30 ), and 125.9 (C-20 ) ppm were appropriately assigned to the phenyl group, and the signal that appeared at 63.3 ppm was attributed to the methine carbon (C-6). Comparing the reaction conditions summarized in Scheme 2, it is clear that method b constitutes the most efcient method to prepare aryl-CIDHMs, while chemoselectivity depends on the reaction conditions. In order to explore the scope and limitations of this novel protocol, as well as to identify the effect induced by other substrates on the formation of the aryl-CIDHPM, the reactions were performed using various arenecarbaldehyde, heteroarenecarbaldehyde, arenedicarbaldehydes, aliphatic aldehydes, b-ketoesters, and cyclic b-diketones, under the conditions of method b (Table 1). A similar behavior was observed in the reactions of arenecarbaldehyde or heteroarenecarbaldehydes, 7beu, with the

R. Hulme et al. / Tetrahedron 64 (2008) 3372e3380 Table 1 Synthesis (10aeu)a

3375

of
O R2 R3

4-aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine

derivates

8a-c O 2 N NH2 9 HCl / AcONa / EtOH 78 C / 4 h R2 R3 N H 10a-u O R1 N H N CN

R1 O H

7a-l, n-r

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
a

R1 C6H5 4-NO2eC6H4 2-NO2eC6H4 3-FeC6H4 2-CleC6H4 Piperonyl 4-BreC6H4 2-(CF3)eC6H4 3-(CF3)eC6H4 4-(OCHF2)eC6H4 2-(OCHF2)eC6H4 5-NO2e2-(OCHF2)eC6H3 4-(NO2)eC6H4
c d

R2

R3

Product 10a 10b 10c 10d 10e 10f 10g 10h 10i 10j 10k 10l 10m 10n 10o 10p 10q 10r 10s 10t 10u

Yieldb (%) 40 68 68 33 38 25 40 35 30 45 50 63 50 45 20 39 34 36 36 25 26

4-Pyridinyl 2-Furanyl 2-Thienyl C6H5 4-(NO2)eC6H4 2-(NO2)eC6H4

C2H5O CH3 C2H5O CH3 C2H5O CH3 C2H5O CH3 C2H5O CH3 C2H5O CH3 C2H5O CH3 C2H5O CH3 C2H5O CH3 C2H5O CH3 C2H5O CH3 C2H5O CH3 CH3O CH3 C2H5O CH3 C2H5O CH3 CH3 C2H5O C2H5O CH3 C2H5O CH3 R2/R3(CH2)3 R2/R3(CH2)3 R2/R3(CH2)3

To determine the structural attributes of these products, several spectroscopic experiments were performed (NMR, MS, and IR). All the data are consistent with the aryl-CIDHPMs 10aeu structure. Thus, only the most important signals of the 2-cyanoimino-3,4-dihydro-1H-pyrimidine fragment, which is common to all aryl-CIDHPMs, are described. The 1H NMR spectrum of 10b (taken as an example) showed two D2Oexchangeable protons at d 10.30 and 9.24 ppm. The former signal appeared as a doublet (3J1,31.4 Hz) and was assigned to NH-1, whereas the latter signal was observed as a doublet of doublets (3J1.4 and 3.6 Hz) and was assigned to NH-3. The doublet signal (3J4,33.6 Hz) observed at 5.37 ppm was assigned to H-4. The 13C NMR spectrum displayed signals at 154.6, 116.2, and 53.0 ppm due to the imino, cyano, and methine, as well as at 100.1 and 147.1 ppm due to the carbons C-5 and C-6, respectively. Further conrmation of the structure of this fragment is provided by gHMBC. Long-range correlations were observed between the carbon atom at 101.1 ppm (C-5) and the protons at 10.36 (H-1), 9.24 (H-3), 2.32 (CH3), and 5.37 (H-4) ppm. In conclusion, the spectroscopic data lead to the unambiguous identication of 4-aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine as tautomer A and rule out the other two possible tautomeric forms B or C (Fig. 2).
4 6

NO2
2

NO2

NO2

O EtO

H
5

O EtO CN N N H N H CN EtO

O N N H N H CN

H N3 N

Reaction conditions: 7 (24 mmol), 8 (24 mmol), 9 (48 mmol), AcONa (24 mmol), EtOH (20 mL), reux, 4 h. b Overall yields. c 4-[4-(2-Cyanoimino-5-ethoxycarbonyl-6-methyl-3,4-dihydro-1H-pyrimidin4-yl)-phenyl]. d 4-[3-(2-Cyanoimino-5-ethoxycarbonyl-6-methyl-3,4-dihydro-1H-pyrimidin4-yl)-phenyl].

N1 H

B
Figure 2. Possible tautomeric forms of 10b.

1,3-dicarbonylic compounds 8aec in the presence of cyanamide 9. The overall yields obtained for the corresponding products 10beu range from modest to good (Table 1, entries 2e21). The highest yields of aryl-CIDHPMs corresponded to the reactions between arenecarbaldehyde containing electronwithdrawing substituents with ethyl acetoacetate (Table 1, entries 2 and 3). However, when cyclohexane-1,3-dione was used, the corresponding aryl-CIDHPMs 10teu yields were rather poor (Table 1, entries 20 and 21). Conversely, when the sterically more demanding isophthalaldehyde was used as reactant, the yield of 10o was low (Table 1, entry 15). The use of aliphatic aldehydes failed to give useful yields of the desired products (data not shown). The reactivity trends found with the cyclic and acyclic 1,3-dicarbonylic compounds are most likely explained by their ketoeenol tautomeric content. In this sense, ethyl acetoacetate is more easily enolized than cyclohexane-1,3-dione because the former is stabilized by a very favorable intramolecular hydrogen bond within a six-membered ring.

Finally, a reasonable and appropriate mechanism is suggested for this MCR, as outlined in Scheme 3. The cyclocondensation reaction of 7aeu and 8aec with 9 that produces the aryl-CIDHPM derivatives 10aeu probably involves N-arylidenecyanoguanidinium IIb as the key intermediate. The nucleophilic addition of cyanamide to the arenecarbaldehyde leads to the aryl cyanoimino compound I, which forms the arylcyanoiminium species Ia after protonation. A subsequent reaction with a second molecule of cyanamide generates the intermediate II, which is in equilibrium with IIa. The cationic intermediate IIb may now undergo nucleophilic attack by the 1, 3-dicarbonyls 8aec, probably under its enol form, to yield the intermediate III, which nally cyclizes to the arylCIDHPMs 10aeu. The proposed mechanism assumes the presence of cyanamide as a nucleophile in a pH range of 5e6 and rules out the cyanamide hydrolysis to urea. This latter conclusion is supported by 13C NMR experiments, as the 13C signal of cyanamide at 116.5 ppm remains unchanged. If hydrolysis occurs, the carbon signal of the urea at 164.7 ppm would gradually appear. Also implicit in the proposed mechanism is that the

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R. Hulme et al. / Tetrahedron 64 (2008) 3372e3380

NH2CN 9 OH H NH2CN 9 N C NH Ia H HN II

R1 H O H

R1

R1 N CN

H H

R1

R1 N N H CN H

R1 N N IIa CN

H2N

7a-l, n-r

I OH

R1 H H HN IIb N H N H CN

R2 R3 8a-c O R2

R1 NH CN N R2

R1 N H N CN R2

R1 N H N CN

R3

O H2N III

R3 N HO H IIIa

R3

N H 10a-u

Scheme 3. Proposed mechanism to obtain aryl-CIDHPMs.

presence of the enol form of 1,3-dicarbonyl favors a conjugate attack on either the N-arylidenecyanoguanidine species IIa or the carbocationic form IIb to subsequently yield the corresponding aryl-CIDHPMs. In this regard, the postulation of IIb as an intermediate would also account for the lack of reactivity observed with aliphatic aldehydes. Compared to aromatic aldehydes, aliphatic aldehydes are less efcient in stabilizing the intermediate carbocation IIb, which ultimately results in a less efcient cyclocondensation reaction to generate aliphatic-CIDHPMs. One important feature of the present protocol is the ability to tolerate variation in two of the four components, making it an MCR of moderate variability. Furthermore, cyclic b-diketone and aromatic aldehyde can also be employed as substrates, in addition to the b-ketoester and aryl dialdehyde or heterocyclic aldehyde, without causing a substantial decrease in the overall yield of aryl-CIDHPM. Interestingly, all aromatic aldehydes that carry either electron-donating or electron-withdrawing substituents reacted under this 4-CR protocol, allowing the production of aryl-CIDHPM in high purity and at low to moderate yields. An additional feature of this procedure is the tolerance of acid-sensitive aldehydes (e.g., furfural 7q) and functional groups (e.g., acetal 7f). Finally, many of the pharmacologically relevant substitution patterns on the 4-phenyl ring can be introduced with high efciency. 3. Conclusion A novel synthesis based on a four-component Biginellitype reaction has been described. The novelty of this multicomponent reaction is the use of cyanamide as a convenient building block to obtain Aryl-CIDHPMs in a very simple and practical way. Furthermore, mild reaction conditions, tolerance of acid-sensitive functional groups, facile purication, moderate overall yields, and exibility make this method an attractive tool to synthesize molecules featuring 2-cyanoimino-3,4-dihydro-1H-pyrimidinic moieties, which might be useful synthons in organic chemistry or important scaffolds in the synthesis of more elaborate compounds with interesting pharmacological properties.

4. Experimental section 4.1. General Melting points (uncorrected) were determined with a Fishere Johns apparatus. IR spectra were recorded on a PerkineElmer 1600 spectrophotometer. 1H, 13C, DEPT, COSY, HETCOR, and gHMBC spectra were recorded on a Varian Mercury 300 instrument in DMSO-d6. Mass spectra (MS) and high-resolution mass spectrometry (HRMS) were obtained on an MStation JMS-700 JEOL spectrometer. Analytical thin-layer chromatography (TLC) was performed using Kieselgel 60 F254 silica gel plates (Merck, Darmstadt, Germany). All reagents, except 2-diuoromethoxy-5-nitrobenzaldehyde that was prepared according to protocols described previously,10a as well as solvents were of reagent grade from Aldrich and were used without further treatment. 4.2. General procedures 4.2.1. 2-Cyanoimino-dihydro-1H-pyrimidines (10aeu) A suspension of the corresponding arenecarbaldehydes 7ael, ner (24 mmol), 1,3-dicarbonyls 8aec (24 mmol), cyanamide 9 (50% in water, 48 mmol), sodium acetate (24 mmol), and concd hydrochloric acid (37%, 0.5 mL) in ethanol (20 mL) was stirred and heated at reux for 4 h. After, the solvent was removed under vacuum, the crude product was ltered and the solid obtained was recrystallized from ethanol to give the pure products. 4.2.1.1. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-phenyl3,4-dihydro-1H-pyrimidine (10a). Yield 40%; mp 259e 261  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.09 (t, J7.0 Hz, 3H), 2.30 (s, 3H), 4.01 (q, J7.0 Hz, 2H), 5.25 (s, 1H), 7.23e7.40 (m, 5H), 9.14 (s, 1H), 10.16 (s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 14.0, 17.3, 53.2, 59.7, 101.2, 116.5, 126.4, 127.9, 128.7, 143.2, 146.0, 154.8, 164.7; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 284; HRMS (EI, 70 eV) found: 284.1282, calcd for C15H16O2N4: 284.1273.

R. Hulme et al. / Tetrahedron 64 (2008) 3372e3380

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4.2.1.2. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(4-nitrophenyl)-3,4-dihydro-1H-pyrimidine (10b). Yield 68%; mp 263e265  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.08 (t, J7.0 Hz, 3H), 2.32 (s, 3H), 4.0 (m, J7.0 Hz, 2H), 5.37 (d, J3.6 Hz, 1H), 7.53 (d, J8.7 Hz, 2H), 8.24 (d, J8.7 Hz, 2H), 9.23 (dd, J3.0, 2.1 Hz, 1H), 10.31 (d, J1.5 Hz, 1H); 13 C NMR (75 MHz, DMSO-d6/TMS): d 14.0, 17.4, 53.0, 59.9, 100.1, 116.2, 124.1, 128.0, 147.1, 150.1, 154.6, 164.4; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 329; HRMS (EI, 70 eV) found: 329.1127, calcd for C15H15O4N5: 329.1124. 4.2.1.3. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(2-nitrophenyl)-3,4-dihydro-1H-pyrimidine (10c). Yield 68%; mp 205e207  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 0.93 (t, J7.0 Hz, 3H), 2.32 (s, 3H), 3.87 (q, J7.0 Hz, 2H), 6.04 (d, J2.7 Hz, 1H), 7.50e7.60 (m, 2H), 7.76 (ddd, J8.7, 7.8, 1.2 Hz, 1H), 7.95 (dd, J8.4, 1.2 Hz, 1H), 9.16 (d, J2.7 Hz, 1H), 10.27 (s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 13.7, 17.3, 48.6, 59.7, 100.1, 115.9, 124.4, 129.3, 129.4, 134.3, 137.8,147.0, 147.4, 153.9, 164.1; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 329; HRMS (EI, 70 eV) found: 329.1198, calcd for C15H15O4N5: 329.1124. 4.2.1.4. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(3-urophenyl)-3,4-dihydro-1H-pyrimidine (10d). Yield 33%; mp 270e272  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.08 (t, J7.2 Hz, 3H), 2.30 (s, 3H), 4.10 (q, J7.2 Hz, 2H), 5.27 (s, 1H), 7.19 (d, J8.4 Hz, 2H), 7.57 (d, J8.0 Hz, 2H), 9.33 (br s, 2H); 13C NMR (75 MHz, DMSO-d6/TMS): d 14.0, 17.3, 52.8, 59.8, 100.5, 113.3 (2JCF21.6 Hz), 114.7 (2JCF20.4 Hz), 116.3, 122.4, 130.8 (3JCF7.9 Hz), 145.9, 146.7, 154.7, 163.7 (1JCF275.0 Hz), 164.5; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 302; HRMS (EI, 70 eV) found: 302.1197, calcd for C15H15O2N4F: 302.1179. 4.2.1.5. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(2-chlorophenyl)-3,4-dihydro-1H-pyrimidine (10e). Yield 38%; mp 243e245  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.02 (t, J7.0 Hz, 3H), 2.31 (s, 3H), 3.93 (q, J7.0 Hz, 2H), 5.68 (d, J0.9 Hz, 1H), 7.25e7.53 (m, 5H), 9.28 (br s, 2H); 13C NMR (75 MHz, DMSO-d6/TMS): d 13.9, 17.2, 51.4, 59.6, 79.2, 100.0, 116.2, 127.8, 129.7, 129.8, 131.9, 140.3, 146.5, 154.0, 164.4; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; HRMS (EI, 70 eV) found: 318.0875, calcd for C15H15O2N4Cl: 318.0884. 4.2.1.6. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-piperonyl-3,4-dihydro-1H-pyrimidine (10f). Yield 25%; mp 264e 266  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.09 (t, J7.0 Hz, 3H), 2.30 (s, 3H), 4.01 (q, J7.0 Hz, 2H), 5.17 (s, 1H), 6.00 (s, 1H), 6.68e6.90 (m, 3H), 9.08 (s, 1H), 10.15 (s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 14.0, 17.3, 52.9, 59.7, 101.1, 101.2, 106.8, 108.2, 116.5, 119.7, 137.0, 146.1, 146.9, 147.4, 154.6, 164.7; IR (KBr) 1641 (C]N), 1679

(C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 328; HRMS (EI, 70 eV) found: 328.1177, calcd for C16H16O4N4: 328.1172. 4.2.1.7. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(4-bromophenyl)-3,4-dihydro-1H-pyrimidine (10g). Yield 40%; mp 264e265  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.08 (t, J7.0 Hz, 3H), 2.30 (s, 3H), 4.10 (q, J7.0 Hz, 2H), 5.23 (s, 1H), 7.19 (d, J8.4 Hz, 2H), 7.57 (d, J8.0 Hz, 2H), 9.17 (br s, 1H), 10.07 (br s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 14.0, 17.3, 52.8, 59.8, 100.6, 116.3, 121.0, 128.7, 131.6, 142.5,146.4, 154.6, 164.5; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 362; HRMS (EI, 70 eV) found: 362.0381, calcd for C15H15O2N4Br: 362.0378. 4.2.1.8. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(2-triuoromethylphenyl)-3,4-dihydro-1H-pyrimidine (10h). Yield 35%; mp 210e211  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 0.91 (t, J7.2 Hz), 2.38 (s, 3H,), 3.89 (q, J7.2 Hz, 2H), 5.70 (s, 1H), 7.46e7.58 (m, 2H), 7.66e7.76 (m, 2H), 8.61 (s, 1H), 10.28 (s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 13.6, 17.8, 50.7, 60.5 101.4, 115.2, 124.2 (1JCF272.1 Hz), 126.5 (3JCF5.7 Hz), 127.1 (2JCF30.6 Hz), 128.3, 128.9, 133.3, 139.2, 145.5, 154.2, 164.0; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 352; HRMS (EI, 70 eV) found: 352.1140, calcd for C16H15O2N4F3: 352.1147. 4.2.1.9. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(3-triuoromethylphenyl)-3,4-dihydro-1H-pyrimidine (10i). Yield 30%; mp 267e268  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.05(t, J7.0 Hz, 3H), 2.32 (s, 3H,), 3.99 (q, J7.0 Hz, 2H), 5.35 (s, 1H), 7.50e7.71 (m, 4H), 9.22 (br s, 1H), 10.15 (br s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 13.8, 17.3, 53.1, 59.8, 100.3, 116.2, 123.5 (3JCF4.5 Hz), 124.1 (3JCF3.45 Hz), 129.0 (2JCF31.7 Hz), 130.1, 130.4, 144.5, 146.8, 154.6, 164.4; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 352; HRMS (EI, 70 eV) found: 352.1134, calcd for C16H15O2N4F3: 352.1147. 4.2.1.10. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(4-diuoromethoxyphenyl)-3,4-dihydro-1H-pyrimidine (10j). Yield 45%; mp 209e211  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.02 (t, J6.9 Hz, 3H), 2.31 (s, 3H), 4.01 (q, J7.0 Hz, 2H), 5.26 (br s, 1H), 7.18 (d, J8.7 Hz, 2H), 7.22 (t, 2JHF74.1 Hz, 1H), 7.29 (d, J8.7 Hz, 2H), 9.14 (br s, 1H), 10.20 (s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 14.0, 17.3, 52.6, 59.8, 100.9, 116.3 (t, 1JCF256.2 Hz), 116.4, 118.9, 128.2, 140.1, 146.3, 150.5, 154.7, 164.6; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 350; HRMS (EI, 70 eV) found: 350.1197, calcd for C16H16O3N4F2: 350.1190. 4.2.1.11. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(2-diuoromethoxyphenyl)-3,4-dihydro-1H-pyrimidine (10k). Yield 50%; mp 247e249  C; 1H NMR (300 MHz, DMSO-d6/ TMS): d 1.04 (t, J6.9 Hz, 3H), 2.28 (s, 3H), 3.93 (q, J7.0 Hz, 2H), 5.54 (s, 1H), 7.15e7.41 (m, 4H), 7.21 (dd,

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JHF75.0, 72.9 Hz, 1H), 8.95 (br s, 1H), 10.14 (br s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 13.8, 17.2, 49.9, 59.6, 99.5, 116.4, 116.5 (t, 1JCF255.1 Hz), 117.3, 125.0, 129.6, 130.1, 133.3, 146.3, 149.0, 154.2, 164.5; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 350; HRMS (EI, 70 eV) found: 350.1176, calcd for C16H16O3N4F2: 350.1190.

4.2.1.12. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(2-diuo romethoxy-5-nitrophenyl)-3,4-dihydro-1H-pyrimidine (10l). Yield 63%; mp 249e250  C; 1H NMR (300 MHz, DMSOd6/TMS): d 1.02 (t, J6.9 Hz, 3H), 2.27 (s, 3H), 3.91 (q, J7.0 Hz, 2H), 5.59 (s, 1H), 7.43 (d, J9.0 Hz, 1H), 7.50 (dd, 2JHF73.5, 72.9 Hz, 1H), 8.08 (d, J3.0 Hz, 1H), 8.29 (dd, J9.0, 2.7 Hz, 1H), 8.97 (br s, 1H), 10.28 (br s, 1H); 13 C NMR (75 MHz, DMSO-d6/TMS): d 13.6, 17.1, 51.1, 59.5, 97.7, 115.7 (t, 1JCF257.3 Hz), 116.1, 117.0, 125.2, 125.9, 133.6, 143.1, 147.2, 153.9, 154.1, 164.1; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 395; HRMS (EI, 70 eV) found: 395.1041, calcd for C16H15O5N5F2: 395.1041. 4.2.1.13. 2-Cyanoimino-5-methoxycarbonyl-6-methyl-4-(4-nitrophenyl)-3,4-dihydro-1H-pyrimidine (10m). Yield 50%; mp 238e240  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 2.32 (s, 3H), 3.55 (s, 3H), 5.38 (s, 1H), 7.52 (d, J8.4 Hz, 2H), 8.23 (d, J8.7 Hz, 2H), 9.27 (s, 1H), 10.34 (s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 17.4, 51.3, 52.8, 99.9, 116.2, 124.1, 127.9, 147.1, 147.3, 149.9, 154.7, 164.9; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 315; HRMS (EI, 70 eV) found: 315.0954, calcd for C14H13O4N5: 315.0968. 4.2.1.14. 2-Cyanoimino-4-[4-(2-cyanoimino-5-ethoxycarbonyl6-methyl-3,4-dihydro-1H-pyrimidin-4-yl)-phenyl]-5-ethoxycarbonyl-6-methyl-3,4-dihydro-1H-pyrimidine (10n). Yield 45%; mp 303e305  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.08 (t, J7.2 Hz, 3H), 1.09 (t, J7.2 Hz, 3H), 2.29 (s, 6H), 4.01 (q, J7.2 Hz, 4H), 5.23 (s, 2H), 7.23 (s, 4H), 9.08 (s, 2H), 10. 13 (s, 2H); 13C NMR (75 MHz, DMSO-d6/ TMS): d 14.6, 18.0, 53.7, 59.4, 101.7, 117.0, 143.5, 146.7, 155.4, 165.3; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 490; HRMS (EI, 70 eV) found: 490.2079, calcd for C24H26O4N8: 490.2077. 4.2.1.15. 2-Cyanoimino-4-[3-(2-cyanoimino-5-ethoxycarbonyl6-methyl-3,4-dihydro-1H-pyrimidin-4-yl)-phenyl]-5-ethoxycarbonyl-6-methyl-3,4-dihydro-1H-pyrimidine (10o). Yield 20%; mp 315e320  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.05 (t, J7.2 Hz, 3H), 1.09 (t, J7.2 Hz, 3H), 2.29 (s, 6H), 3.99 (q, J7.2 Hz, 4H), 5.23 (s, 2H), 7.23 (s, 4H), 9.12 (s, 2H), 10.15 (s, 2H); 13C NMR (75 MHz, DMSO-d6/TMS): d 14.0, 17.2, 53.2, 59.7, 101.1, 116.4, 124.3, 124.5, 126.0, 128.9, 143.7, 146.1, 154.7, 154.8, 164.5; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 490; HRMS (EI, 70 eV) found: 490.2069, calcd for C24H26O4N8: 490.2077.

4.2.1.16. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(4-pyridinyl)-3,4-dihydro-1H-pyrimidine (10p). Yield 39%; mp 249e251  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.10 (t, J7.0 Hz, 3H), 2.30 (s, 3H), 4.10 (q, J7.0 Hz, 2H), 5.26 (s, 1H), 7.23 (d, J4.8 Hz, 2H), 8.57 (d, J4.8 Hz, 2H), 9.24 (s, 1H), 10.30 (s, 1H); 13C NMR (75 MHz, DMSO-d6/ TMS): d 14.0, 17.4, 52.3, 59.9, 99.9, 116.2, 121.4, 147.2, 150.2, 151.1, 154.9, 164.5; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 285; HRMS (EI, 70 eV) found: 285.1215, calcd for C14H15O2N5: 285.1226. 4.2.1.17. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(2-furanyl)-3,4-dihydro-1H-pyrimidine (10q). Yield 34%; mp 244e 245  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.12 (t, J7.0 Hz, 3H), 2.25 (s, 3H), 4.08 (q, J7.0 Hz, 2H), 5.30 (d, J2.7 Hz, 1H), 6.16 (d, J3.3 Hz, 1H), 6.37 (dd, J3.3, 1.8 Hz, 1H), 7.58 (dd, J1.8, 0.6 Hz, 1H), 9.15 (d, J2.7 Hz, 1H), 10.22 (s, 1H); 13C NMR (75 MHz, DMSOd6/TMS): d 14.1, 17.3, 47.0, 59.8, 98.8, 106.4, 110.5, 116.3, 142.8, 147.0, 154.2, 155.3, 164.4; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 274; HRMS (EI, 70 eV) found: 274.1052, calcd for C13H14O3N4: 274.1066. 4.2.1.18. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(2-thienyl)-3,4-dihydro-1H-pyrimidine (10r). Yield 36%; mp 255e 256  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.15 (t, J7.0 Hz, 3H), 2.28 (s, 3H), 4.08 (q, J7.0 Hz, 2H), 5.52 (s, 1H), 6.92 (d, J3.6 Hz, 1H), 6.97 (dd, J4.8, 3.6 Hz, 1H), 7.42 (d, J4.5 Hz, 1H), 9.31 (s, 1H), 10.31 (s, 1H); 13 C NMR (75 MHz, DMSO-d6/TMS): d 14.1, 17.2, 48.5, 59.9, 101.7, 116.3, 124.3, 125.5, 127.0, 146.5,146.7, 155.0, 164.4; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 290; HRMS (EI, 70 eV) found: 290.0840, calcd for C13H14O2N4S: 290.0837. 4.2.1.19. [5-Oxo-4-phenyl-3,4,5,6,7,8-hexahydroquinazolin2(1H)-ylidene]cyanamide (10s). Yield 36%; mp 300  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.72e206 (m, 2H), 2.20e2.40 (m, 2H), 2.45e2.65 (m, 2H), 5.26 (d, J3.6 Hz, 1H), 7.19e7.36 (m, 5H), 9.12 (d, J3.6 Hz, 1H), 10.46 (s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 20.4, 25.4, 36.2, 50.9, 109.5, 116.2, 126.4, 127.7, 128.6, 143.0, 152.1, 154.7, 193.6; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 266; HRMS (EI, 70 eV) found: 266.1173, calcd for C15H14ON4: 266.1168. 4.2.1.20. [4-(4-Nitrophenyl)-5-oxo-3,4,5,6,7,8-hexahydroquinazolin-2(1H)-ylidene]cyanamide (10t). Yield 25%; mp 300  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.65e2.05 (m, 2H), 2.10e2.40 (m, 2H), 2.45e2.70 (m, 2H), 5.39 (s, 1H), 7.51 (d, J9.0 Hz, 2H), 8.21 (d, J8.7 Hz, 2H), 9.22 (s, 1H), 10.59 (s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 20.3, 25.5, 36.1, 50.9, 108.5, 115.9, 123.9, 127.9, 146.9, 150.0, 152.8, 154.6, 193.5; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 311;

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3379

HRMS (EI, 70 eV) found: 311.1006, calcd for C15H13O3N5: 311.1018. 4.2.1.21. [4-(2-Nitrophenyl)-5-oxo-3,4,5,6,7,8-hexahydroquinazolin-2(1H)-ylidene]cyanamide (10u). Yield 26%; mp 270e 275  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.65e2.0 (m, 2H), 2.05e2.35 (m, 2H), 2.41e2.65 (m, 2H), 6.01 (s, 1H), 7.19e7.36 (m, 5H), 9.13 (s, 1H), 10.56 (s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 20.4, 25.4, 36.0, 47.5, 108.5, 115.7, 124.1, 129.0, 129.7, 133.8, 137.2, 147.8, 152.4, 153.9, 193.4; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cm1; MS m/z 312; HRMS (EI, 70 eV) found: 312.1100, calcd for C15H14O3N5: 311.2954. 4.2.2. N-(2-Imino-6-phenyl-1,3,5-oxadiazinan-4-ylidene)cyanamide (11) Benzaldehyde 7a (24 mmol), cyanamide 9 (50% in water, 48 mmol), sodium acetate (24 mmol), and concd hydrochloric acid (37%, 0.5 mL, pH w5e6) were stirred and heated in the absence of solvent at 90  C for 2 h. After being concentrated under vacuum, the residue was ltered, resuspended in hot ethanol, and cooled. The precipitate was ltered to yield the pure product: yield 50%; mp 300  C; 1H NMR (300 MHz, DMSOd6/TMS): d 5.63 (d, J2.4 Hz, 1H), 7.30e7.47 (m, 5H), 8.63 (d, J2.4 Hz, 1H), 9.68 (br s, 1H), 10.47 (br s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 63.3, 115.7, 125.9, 128.8, 128.9, 140.4, 150.6, 156.6; MS m/z 215; HRMS (EI, 70 eV) found: 215.0809, calcd for C10H9ON5: 215.0807. 4.2.3. 5-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (12) Benzaldehyde 9a (24 mmol), cyanamide 9 (50% in water, 48 mmol), ammonium chloride (24 mmol), and p-toluenesulfonic acid (24 mmol) in ethanol (20 mL) were stirred and heated to reux for 2 h. Subsequently, ethyl acetate 8a (24 mmol) was added to the mixture, which was heated and stirred for 3 h, and then concentrated, cooled, and ltered. The residue was washed with either isopropyl alcohol or ethanol and ether. The solid was suspended in acetone and ltered. The product was collected after elimination of acetone and recrystallized from ethanol obtaining the pure product: yield 59%; mp 203e205  C; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.08 (t, J6.9 Hz, 3H), 2.24 (s, 3H), 3.97 (q, J7.2 Hz, 2H), 5.13 (d, J3.3 Hz, 1H), 7.0e7.50 (m, 5H), 7.77 (dd, J3.3 and 2.1 Hz, 1H), 9.22 (d, J1.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 14.1, 17.8, 53.9, 59.2, 99.2, 126.2, 127.3, 128.4, 144.8, 148.4, 152.1, 165.3; MS (EI, 70 eV) m/z 260.2908. Acknowledgements F.D. would like to acknowledge CONACyT (Grant 44038Q) and SIP/IPN (Grant 20060055, 20070617) for nancial support. R.H. is grateful to CONACyT for a graduate scholarship and a Research Fellowship IN1-69, FESC-UNAM. I.V.-H. is a fellow of the EDI/IPN and COFAA/IPN programs. The authors are grateful to Ms. Ana P. Contreras Rojas (McGill University, Montreal Canada) for reviewing the manuscript.

References and notes

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